A Novel Mutation in STAT3 in a Family with Autosomal Dominant Hyper-IgE Syndrome

Abstract

RATIONALE: To identify the molecular basis of disease in a family presenting with increased susceptibility to infections. METHODS: Extended family history was obtained in a 31-year-old female, her 5-year-old son, and her 53-year-old mother presenting with a history of increased infections. Blood was sent for routine immunologic evaluations including quantitative immunoglobulins, complete blood count, and neutrophil oxidative burst. Blood samples obtained from the son, mother and grandmother, were analyzed for STAT3 mutations by cDNA sequencing. RESULTS: History was remarkable for staphylococcal skin, bone and blood infections, retained primary teeth, scoliosis, hyperextensibility, fungal skin infections and eczema. Most infections occurred in the mother when she was young, improving with age. Extended family history was positive for multiple family members being affected by lung, skin, and other infections, spanning four generations. Immunologic workup was unremarkable except for slightly elevated IgE levels (2296, 682 and 663 IU/mL in grandmother, mother, and son). Facial morphometric features of hyper-IgE syndrome were not apparent. Sequencing of STAT3 cDNA revealed a novel heterozygous mutation, c1003C>T, in a highly conserved and exposed region of the DNA binding domain resulting in arginine to tryptophan substitution at amino acid position 335 in three generations. CONCLUSIONS: R335W STAT3 mutation was associated with a phenotypically distinct variant of hyper-IgE syndrome with less coarse facial features, milder IgE elevations, and a milder presentation of immunodeficiency primarily in childhood in the family members evaluated in this study. However, variability in clinical severity among extended family members suggests presence of other modifying factors in addition to the STAT3 mutation.